3. MECHANISTIC VIEWS OF STEREOSELECTIVE SYNTHESIS OF TRIAND TETRA-SUBSTITUTED ALKENES, PART II; THE ORGANIC CHEMISTRY NOTEBOOK SERIES, A DIDACTICAL APPROACH, Nº 4.

(1)

Bravo et Vila .

MECHANISTIC VIEWS OF STEREOSELECTIVE SYNTHESIS OF TRI-

AND TETRA-SUBSTITUTED ALKENES, PART II; THE ORGANIC

CHEMISTRY NOTEBOOK SERIES, A DIDACTICAL APPROACH, Nº 4

José A. Bravo*, José L. Vila

Department of Chemistry, Laboratorio de Síntesis y Hemisíntesis, Instituto de Investigaciones en Productos Naturales IIPN, Universidad Mayor de San Andrés UMSA, P.O. Box 303, Calle Andrés Bello s/n, Ciudad Universitaria Cota Cota, Tel. 59122792238, La Paz, Bolivia

Keywords: Organic Chemistry, Stereoselective synthesis, Alkenes, Addition reaction, Mechanisms of Reactions.

ABSTRACT

This is the complementing part of the previously published: “Mechanistic views of stereoselective synthesis of tri- and tetra-substituted alkenes, part I; The Organic Chemistry Notebook Series, a Didactical Approach, Nº 3”. As underlined in three previous papers the presentation of synthesis works in a verbal and graphical succinct manner, needs a didactical approach. Isomerically pure tri- and tetra-substituted alkenes are difficult to obtain as shown in several publications. We used a series of reactions to synthesize tri- and tetra-substituted alkenes as reviewed by W. Carruthers, and we have proposed didactical and mechanistic views for the reviewed reactions. These two latest approaches are included in the synthetic methods reviewed by W. Carruthers with respect to the “Formation of carbon-carbon double bonds”. Spanish title: Vistas mecanísticas de síntesis estereoselectivas de alquenos tri y tetrasubstituidos, Parte II, Serie: El cuaderno de notas de química orgánica, un enfoque didáctico, Nº4.

*Corresponding author: [email protected]

ANALYSIS AND MECHANISTIC PROPOSALS

As academics we are concerned with the didactical importance of covering the needs of debutant students in organic synthesis. This is the fourth study in: “The Organic Chemistry Notebook Series, a Didactical Approach” [1-3]. The present article is the completion of the analytical and didactical approach to stereoselective synthesis of tri- and tetra-substituted alkenes as reviewed by W. Carruthers [4], and illustrated mechanistically by J. Bravo and J. Vila [3]. Tri- and tetra-substituted alkenes are difficult to obtain. Authors [4] mentioned other methods signaled as useful for the stereospecific synthesis of alkenes starting with alkynes. The procedure starts with alkenylalanes and alkenylboranes. The first are obtained by hydroalumination of alkynes with e.g. diisobutylaluminium hydride. The addition is cis type, giving rise to Z-alkenylalanes. The Z-alkenylalanes react with halogens with retention of configuration to afford alkenyl halides. The halogen atoms can be replaced by alkyl groups by means of reacting with an organocopper reagent. Iodination of the alane obtained from reaction of 1-hexyne with diisobutylaluminium hydride makes possible the (E)-1-iodo-1-hexene. 3-hexyne gives (E)-3-iodo-3-hexene [4]. See Figure 1 for the reactions reviewed by W. Carruthers [4].

C H C

C4H9 _C _C

H

C4H9 H

Al(iso C4H9)2 (iso-C₄H₉)2AlH

C7H16

(1) I2, THF, -50 o

C (2) H3O

+

C C H

C4H9 H

I

(74%)

C C2H5 C

C2H5 _C _C

C2H5

H

C₂H₅

Al(iso C₄H₉)₂ (iso-C4H9)2AlH

C7H16

(1) I2, THF, -50 o

C (2) H3O

+

(72%) C C C2H5

H

C₂H₅

I

Figure 1. Obtention of alkenyl halides via alkenylalanes [(E)-1-iodo-1-hexene and (E)-3-iodo-3-hexene; reviewed by W.

(2)

Bravo et Vila .

Figure 2 shows the mechanistic proposal for these reactions.

C C:

-H

H C H

C

(iso-C4H9)2Al H (iso-C4H9)2Al+

H (iso-But)2Al

H

C:- H

H

(iso-C4H9)2Al++ O.. +I- +_I+

H

H I

O+

Al(i-But)2 ..

+ I -+

optionally:

O H (iso-But)2Al

-H

+ _I+

O+

Al(i-But)2 ..

+ I

-+ O+

Al-_(i-But) 2

I

.. ..

(E)-1-iodo-1-hexene 1-hexyne

1st 2nd

C C

(iso-C4H9)2Al H

O (iso-But)2Al

-H

+ _I+

(iso-But)2Al

H C C:

-H

(iso-C4H9)2Al+

O..

+

.. _I

2

H I

O+

Al(i-But)2 ..

+ I -+

(E)-3-iodo-3-hexene 3-hexyne

O+

Al-(i-But)2

I

..

1st 2nd

Figure 2. Synthesis of (E)-1-iodo-1-hexene and (E)-3-iodo-3-hexene, mechanistic views

Alternatively, Z- and E-1-halogenoalkenes can be obtained from terminal acetylenes by means of the use of E -alkenylboronic acids which can be synthesized by reaction of terminal acetylenes with catecholborane and subsequent hydrolysis [4]. Boronic acids react with sodium hydroxide to replace the boronic acid group by iodine to afford E-1-iodoalkene; retention of configuration occurs [4]. If the reaction is carried out with bromine and base, the substitution result implies inversion; Z-1-bromoalkene is obtained [4]. In both reactions, the stereoselectivity is high; for example, 1-octyne gave (Z)-1-bromo-1-octene (85% yield, 99% stereoselectivity), and 1-hexyne gave (E )-1-iodo-1-hexene [4]. Figure 3 and 4 show the global reactions and the mechanistic approach, respectively.

C H

C

C6H13 _C _C

C6H13

H _B

H _{(1) Br}

2, CH2Cl2 (2)

(85%; 99% Z)

O BH O

1)

H3O+

2) NaOCH_CH 3

3OH

C C C6H13

H _H

Br C H

C

C4H9 _C _C

C4H9

H _B

H

OH HO

(1) I2 (2)

(89%; more than 99% E)

O BH O

1)

H3O+

2) NaOH

C C C4H9

H _I

H

C C

R

H _B

H _Br

2

NaOCH3

C C

R

H H

Br Br

B rotate 120 o

C C

R

H Br

B Br

H C C

R

H _H

Br CH3O

-Figure 3. Obtention of (E)-1-halogenoalkenes from terminal acetylenes via E-alkenylboronic acids. Inversion of configuration

(3)

Bravo et Vila .

Inversion of configuration in brominating is explained by the trans-addition of Br2 to the double bond and

ulterior trans-elimination of boron and bromine due to NaOCH3 ([4], Figure 3).

+_{C C} B

H

H O O C H

C

1-hexyne O B O H

_ C C

B H

O O H

H3O+

C C B

H

O O H

H H2O

+ C C

B H

O O H

H

O+_H

2

H2O C C

B H

O O+

H

OH H

H2O

C C B

H

O O H

H

OH + H+

OH

Na+_OH

-C C B

H OH

HO H

OH Na+

_ C C:

H

H _

Na+

I

-+ I+

C C H H

I

Na+

I-₊ ₊

+ OH

OH

C H C C6H13

O B O H

C C C6H13

B H

H O O _ +

B(OH)3

1-octyne

C C

H B

H

O O C6H13

C C

H B

H

O O C6H13

Br+

Br

-C -C-:

H B

H

O O C6H13 Br

Br+

Br+ Br

-C C H

B H

O O C6H13 Br

Br

C C C6H13

H H

Br Br

B

rotate 120o

C C C6H13

H Br

B Br

H

C C

H _H

Br C6H13 Br

B O

O

Na+_O-_CH 3

C C

H _H

Br C6H13 Br

B O

O OCH3

_ Na+

C C

H H

Br C6H13 Br

Na+

B O

O CH3O

.. _

+ C C

H H

Br C6H13

NaBr +

O BOCH3

O +

Figure 4. Obtention of (E)-1-halogenoalkenes from terminal acetylenes via E-alkenylboronic acids. Inversion of configuration

during bromination, mechanistic view

(4)

Bravo et Vila .

are converted into isobutane in the hydrolysis step, and do not interfere with the isolation of the products’ (W. Carruthers [4]). See Figure 6.

C CH3

C

CH3 C C

CH3

H _Al(iso-C₄_H₉₎₂ CH3

(iso-C4H9)2AlH

CH3Li, ether, -30oC

C C

CH3

H _Al(iso-C₄_H₉₎₂ CH3

CH3

- Li+

CO2, H3O+

C C CH3 H _CO 2H CH3 (76%)

CO2, H3O+

C C

H

CH3 CO2H

CH3

(72%) (1) paraformaldehyde

(2) H3O+

C C

H

CH3 CH2OH

CH3

(68%) 2-butyne

Figure 5. Obtaining of αβ-unsaturated carboxylic acids and allylic alcohol from aluminates; reviewed by W. Carruthers [4]

C C: -CH3

H

CH3 C

C

(iso-C4H9)2Al H

(iso-C4H9)2Al+

2-butyne

C C CH3

H

CH3 Al(iso-C4H9)2

Li+_CH 3

-C C CH3

H

CH3 Al(iso-C4H9)2

_ Li+ C C CH3 H CH3 Al(iso-C4H9)2

CH3 _ Li+ C C: CH3 H

CH3 _Al(iso-C 4H9)2 CH3 + O C O C C CH3 H CH3 O O Li+ _

H3O+

C C CH3 H CH3 O HO

LiOH + Al(iso-C4H9)2 CH3

+ H+

cis-crotonic acid

C C: -CH3

H CH3

C C

2-butyne

C C CH3

H _CH

3 Al(iso-C4H9)2

Li+ CH3

-+ _ Li+ C C H CH3 CH3 Al(iso-C4H9)2

CH3

_ Li+

C C: CH3

H CH3

Al(iso-C4H9)2 CH3

2-butyne

C C CH3

H _CH₃

O- O

Li+

H3O+

O C O

C C CH3

H CH3

O HO

LiOH + Al(iso-C4H9)2 CH3

+ H+

trans-crotonic acid +

C C: -CH3

H CH3

C C

2-butyne

C C CH3

H _CH

3 Al(iso-C4H9)2

Li+ CH3

-_ Li+ C C H CH3 CH3 Al(iso-C4H9)2

CH3

_ Li+

C C: CH3

H CH3

Al(iso-C4H9)2 CH3 CH2 O HO H n n-1

O CH2+

H ₊ O CH2+

formaldehyde CH2OCH2

O

-_O H

n-1 CH2OCH2

O HO H paraformaldehyde CH2 O HO H n solvolysis paraformaldehyde Solvolysis

n-1 O=CH2 formaldehyde C C

CH3

H CH3

H O

-H

Li+ H3O +

C C CH3

H CH3

H

OH

H

LiOH Al(iso-C4H9)2 CH3

+ + + H+

n-1

C4H9 Al C4H9 CH3

+ H2O C4H9 Al- C4H9 CH3 O+H2

C4H9 Al CH3 O+_H 2

+ -C4H9 C4H9 Al CH3 OH

+ C4H10 isobutane

H2O _C 4H9 Al

-CH3 OH

O+H2

+ -C4H9 OH

Al CH3

O+H2

+ C4H10 OH

Al CH3

OH

isobutane

(5)

Bravo et Vila .

In contrast with alkenylalanes, alkenylboranes (obtainable from hydroboration of alkynes) exhibit a different comportment. Under iodination, no iodide is produced, instead, the stereospecific transfer of one alkyl group from boron to its vicinal carbon occurs. This provides an alternative stereospecific synthesis of substituted alkenes [4]. In this way, iodine and sodium hydroxide added to the alkenylborane obtained after hydroboration of 1-hexyne with dicyclohexylborane, conducts to (Z)-1-cyclohexyl-1-hexene (75% yield). See Figure 7 for the reaction reviewed by W. Carruthers [4]. Figure 8 shows the corresponding mechanistic view.

C H

C

C4H9 C C

C4H9

H

H B(C6H11)2 (C6H11)2BH

C C

H

C4H9 H

B C6H11

C6H11

I+ 1-hexyne

I2, NaOH

I

-C C

H C4H9

H B

I

C6H11

I

C6H11

=

C C

H C4H9

C6H11

H I

B I C6H11

C C

C4H9

H H

C6H11

(75% Z)

Figure 7. Synthesis of (Z)-1-cyclohexyl-1-hexene employing 1-hexyne as starting material and applying alkenylborane and

subsequent addition of iodine; reviewed by W. Carruthers [4]

C H C

C4H9 C+ C

C4H9 H B -H

1-hexyne H11C6

B

H _C

6H11

C C C4H9

H

H B

+Na++ OH

-I+

I- +

C C+ C4H9

H

H B

I

: .. : : .. :

C C C4H9

H

H B

I : .. +

I

-C -C C4H9

H B

-I I

H

: .. +

C C C4H9

H

B I

I

H

C C C4H9

H H

B+ I

+ + I-= _BI 2C6H11

=

C4H9 C C

H

H I

B I

=

C C C4H9

H

H I

B I

(75% Z)

subsequent addition of iodine; mechanistic views

Similarly, 3-hexyne is transformed in (Z)-3-cyclohexyl-3-hexene [4]; Figure 9 shows the corresponding mechanism. The “anti” elimination of boron and the iodine atom, reassures the stereoselectivity of the observed alkenic product in the alkene-forming step [4].

C Et C

Et _C+ _C

C2H5 C2H5 B -H

3-hexyne H11C6

B

H _C

6H11

C C C2H5

H

C2H5

B ₊

+ Na+

OH

-I+

I- +

C C+ C2H5

H

C2H5 B

I

: .. : : .. :

C C C2H5

H

C2H5 B

I : .. +

I

-C -C C2H5

H B

-I I

C2H5

: .. +

C C C2H5

H

B I

I

C2H5

=

C2H5 C C H

C2H5 I

B I

=

(6)

_{: ..} _{: ..} Bravo et Vila .

C C C2H5

H C2H5

B+ I

+ + I-= _BI 2C6H11 C C

C2H5 H

C2H5 I

B I

(85% Z) (Z)-3-cyclohexyl-3-hexene

subsequent addition of iodine; mechanistic view (Cont.)

Dialkylvinylboranes can be synthesized from dialkylhaloboranes and an internal alkyne in the presence of lithium aluminium hydride. These can react with iodine in the presence of methoxide to produce trisubstituted alkenes, stereoselectively. The two substituents of the alkyne are trans to each other [4]. (Z)-3-methyl-3-pentene was obtained from 2-butyne as Figure 10 shows [4]. The mechanism includes the iodine complex already exposed in Figures 7 to 9; see Figure 11.

C CH3

C

CH3 _C _C

(C2H5)2B

CH3 CH3

H

(C2H5)2BBr _I

2, NaOH

C C

CH3

C2H5 CH3

H

2-butyne 1/4 LiAlH4, THF CH3OH, -78º C

(74%)

Figure 10. Synthesis of (Z)-3-methyl-2-pentene, a tri-substituted alkene with the two original substituents in alkyne located in

trans to each other; reviewed by W. Carruthers [4]

:C -C CH3 _CH₃

H C

C

H3Al- H

2-butyne

C C B

-CH3

H CH3 Br C2H5

C2H5 C C

B

CH3

H

CH3 C2H5 C2H5

Li+

AlH3 H5C2

B Br _C

2H5

Li+

AlH3 LiBr + + _I+

: .. :

I C+

C B

CH3

H

CH3 C2H5 C2H5

: .. : I

C C B

CH3

H

CH3 C2H5 C2H5

.. : +

+ Na+OH -I

-I C C B

-CH3

H

CH3 C2H5

I _C

2H5

.. : +

I C C B CH3

H CH3 I

C2H5 C2H5

: .. :

=

I C C CH3 C2H5

H CH3 B

Et I

: .. :

C C+ CH3 C2H5

H CH3 B

-Et I

I

C C CH3

C2H5

H

CH3 +

(Z)-3-methyl-2-pentene

I2BEt

Figure 11. Synthesis of (Z)-3-methyl-2-pentene, a tri-substituted alkene with the two original substituents in alkyne located in

trans to each other; mechanistic views

Trisubstituted alkenes are also obtained from terminal alkynes by way of the corresponding 1-alkenyl iodides. Iodide is treated by butyl-lithium, trialkylborane and iodine. The trisubstituted alkene possesses the iodine of the alkenyl iodide replaced by an alkyl group coming from the borane with retention of configuration. ‘The stereochemistry of the product requires syn elimination of R2BI’ [4,7,8]. Figures 12 and 13 explain this synthesis.

C H

C

C6H13 C C

C6H13

C2H5 Cu(CH3)2S.MgBr2

H

2-butyne

C2H5MgBr

CuBr.(CH3)2S

I2 _C _C

C6H13

C2H5 I

H

(1) C4H9Li

(2) (C2H5)B, -78 o

C

Figure 12. Trisubstituted alkene synthesis by iodination and subsequent treatment with butyl-lithium, trialkylborane and iodine;

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Bravo et Vila .

C C

C6H13

C2H5 B-(C2H5)3

H

Li+ I2

C C

C6H13

C2H5 C2H5

H

(75%; 95% stereochemically pure)

reviewed by W. Carruthers [4] (Cont.)

C C: -Et

C6H13 H

C H

C C6H13

2-butyne

Et-_Mg+_Br

;

Me S.._.. Me ₊ Cu+₊Br- Me S+ Me Cu

.. + Br-= CuBr.Me2S

C C

Et

C6H13 H

Cu

+ Me S Me

..

.. +Mg+2+2Br -Mg+2_Br

-+ +

MgBr2

Me S Me

C C

Et

C6H13 H

Cu

MgBr2 .. ..

=

C C Et

C6H13 H

CuMe2S.MgBr2

I

-I+

CuMe2S.MgBr2

C C C6H13

I

I H C2H5

C C

Et

C6H13 H

I

+

CuMe2S.MgBr2

I

-+ C4H9

-Li+

C C-: Et

C6H13 H

Li+

C4H9I

(C2H5)3B

C C

Et

C6H13 H

-_BEt 3

Li+

I2

I+ : .. :

Li+

I C+ C Et

C6H13 H

-_BEt 3

: .. :

Li+

I C C Et

C6H13 H

-_BEt

Et Et

.. :+

BEt2

C C C6H13

I

Et

H C2H5

I

-BEt2

C C C6H13

I

Et

H C2H5

I

-B-Et2

C C C6H13

I

Et H C2H5

I

C C

Et

C6H13 H

Et

+ BIEt2 + LiI

Li+

mechanistic views

The synthesis of trisubstituted alkenes can be achieved using allylic alcohols as starting material. This depends in its critical phase on the stereoselective epoxidation of allylic alcohols. Hence, (Z)-6-methyl-5-undecene was obtained by oxidation of the allylic alcohol 1_with_t_{-butyl hydroperoxide and vanadium catalyst to selectively give rise to}

erythro-epoxide 2_{that at its turn was converted to the vicinal diol}3_{thanks to interaction with lithium dibutylcuprate.}

Stereospecific deoxygenation of the diol could be possible by interaction with N,N-dimethylformamide dimethyl acetal. The dioxolane derivative obtained is then decomposed by heating and by adding acetic anhydride to give rise to the Z-alkene [4]. The vanadium-t-butyl hydroperoxide react with the C=C of allylic alcohols making possible selective epoxidations. Reaction of 1_{with t-C}₄_H₉_{OOH in the presence of vanadium acetylacetonate as catalyst gave}2

almost exclusively [4,9,10]. See Figures 14 and 15.

C4H9

HO CH3

1

t-C4H9OOH

VO(acac)2

C4H9 O

HO CH3

H

2

Li(C4H9)2Cu

ether, -26oC

C4H9 OH

HO CH3

H C5H11

3

(CH3)2NCH(OCH3)2, 25 o

C

C4H9 C5H11

O O

H H3C

H N(CH3)2

(CH3CO)2O

130oC

C4H9 C5H11

H CH3

(8)

Bravo et Vila .

acac : CH3 C CH2

O

C CH2

-O

VO(acac)2 :

CH2 CH3 C CH2 O C O CH2

CH3 C CH2

O

C O V

O CH2

CH3 C CH2

O

C O

-H O O t-bu H H CH3 HO H VOacac2 =

(acac)2OV

H O O t-bu H H CH3 HO H

..

(acac)2OV

H O O t-bu H H CH3 HO H +

_..

..

_ = (acac)2OV

H O O t-bu H H CH3 HO H +

..

_ = (acac)2OV

H O O t-bu H H CH3 HO H + ...... .. _ + .. .. .. .. _

(acac)2OV O _H

H H CH3 HO H O t-bu = .. .. ..

(acac)2OV O

H H CH3 HO H HO t-bu ..

C4H9 O

HO CH3

H

Li+_{, Cu}+ (C4H9)2

-.. .. O H H CH3 HO H

C4H9

-=

CH3

O

C4H9

HO H erythro = .. .. O H

C4H9 CH3 HO H H .. _ Li+

C4H9

O

-HO CH3

H

C5H11

Li+ =

C4H9 _O

-HO CH3

H

C5H11

Li+

CH3

Li+_O- _C 5H11 C4H9

HO H

= =

OH H

C4H9

C5H11 OLi

CH3

OH

H

C4H9

C5H11 OLi

CH3

H2O OH

H

C4H9

C5H11 OH

CH3

+ LiOH + CH3

N OCH3

CH3 H

OCH3

H+ CH3

N OCH3

CH3 H

O+CH3

H

..

=

C4H9 _OH

HO CH3

H

C5H11

+

C4H9

OH HO

CH3

H

C5H11

..

O+CH3

CH3O

NMe2

H

C4H9

O+H HO

CH3

H

C5H11

CH3O

NMe2

H

..

+

MeOH

C4H9

O HO

CH3

H

C5H11

Me2N

H

O+HCH3

..

C4H9

O H+O

CH3

H

C5H11

Me2N H

..

+ MeOH

C4H9

O H+O

CH3 H

C5H11

Me2N H

.. .. .. + MeOH O O C4H9

C5H11

H Me NMe2

H

-H+ _(CH₃_CO)₂_O+_H

O

-NMe2 O

C4H9 C5H11

H Me

HO

NMe2 O

C4H9 C5H11

H Me +

Figure 15. Trisubstituted alkene synthesis from allylic alcohol; mechanistic views

ACKNOWLEDGEMENTS

The authors express their gratitude to Prof. Eduardo Palenque from the Department of Physics, Universidad Mayor de San Andrés, for his bibliographic support.

REFERENCES

(9)

Bravo et Vila .

2. Bravo, J.A., Mollinedo, P., Peñarrieta, J.M., Vila, J.L.2013_{, Bol. J. of Chem}_.,₃₀_{, 24-41} (http://www.bolivianchemistryjournal.org, 2013)

3. Bravo, J.A., Vila, J.L.2014_{, Bol. J. of Chem}_.,₃₁_{, 61-67 (}_{http://www.bolivianchemistryjournal.org}_{, 2014)}

4. Carruthers, W. Some Modern Methods of Organic Synthesis, Cambridge University Press, 3rd ed., 1987_{, Worcester, U.K., pp.} 148-156, 374.